A circular RNA vaccine induces durable and cross-protective immunity against Neisseria meningitidis serogroup B in mice.

Neisseria meningitidis serogroup B (MenB) remains a major global cause of meningitis and septicemia. However, MenB vaccine development is hindered by antigenic diversity and manufacturing challenges associated with outer membrane vesicles (OMVs) or lipoproteins in resource-limited settings. Here, we engineered a high-purity circular RNA (circRNA) vaccine encoding a bacterial-derived, sequence-optimized fusion antigen of factor H binding protein (fHbp) and Neisserial heparin-binding antigen (NHBA) (fHbp-NHBA), which preserves key bactericidal epitopes in eukaryotic systems. The vaccine elicited potent functional antibody responses by serum bactericidal assay (SBA) using human complement and potent IFN-γ-secreting CD8 + T-cell responses. Crucially, the circRNA vaccine at a low dose provided complete protection and reduced bacteremia against lethal MenB challenge and demonstrated cross protection against a panel of prevalent strains in China. Both single- and two-dose regimens of the circRNA vaccine induced durable immune responses, and the two-dose immunization achieved strain coverage comparable to that of licensed MenB vaccines. Moreover, sera adoptively transferred from the circRNA-immunized group to neonatal rat pups dramatically reduced bacterial loads in blood. This study establishes a foundation for circRNA-based vaccines against bacterial pathogens.